Continuous renal replacement therapy (CRRT) is well established as a modality for the management of renal failure in the critically ill patient. When CRRT was first developed, the major indications for use were fluid and solute removal associated with renal failure, such as those patients developing acute renal failure (ARF). Acute renal failure (ARF) is rarely an isolated process but is often a complication of underlying conditions such as sepsis, trauma, and multiple-organ failure in critically ill patients. As such, concomitant clinical conditions significantly affect patient outcome. CRRT applications have developed over time to include use for patients with chronic renal failure (CRF) and for other indications. Continuous renal replacement therapy (CRRT) has recently emerged as the dialysis technique of choice for critically ill patients with acute renal failure (ARF). There are several types of CRRT therapy, including but not limited to, continuous venovenous hemofiltration (CVVH). CRRT is generally recognized as offering significant advantages to intermittent dialysis for fluid and metabolic control (1). Additionally, high ultrafiltration rates (greater than or equal to 35 ml/kg/hr) using CRRT, such as CVVH, have been associated with improved patient survival (2).
During CRRT procedures, solutions must be added to keep the blood flowing through the CRRT device from clotting. Heparin sodium is the most common anticoagulant used for CRRT. Systems are frequently flushed with dilute heparin through the system during the priming procedure (5,000-10,000 U/L normal saline) followed by a constant delivery of heparin for the duration of therapy. For many years, it was the anticoagulant of choice for all forms of dialysis that used a blood path. However, as CRRT was applied to the more profoundly ill patients, heparin was found to be associated with complications caused by coagulation disorders seen in the critically ill. Side effects that may be observed include, but are not limited to, systemic anticoagulation, thrombocytopenia and suppressed aldosterone secretion. The effects on systemic coagulation make heparin administration very problematic in patients with gastrointestinal bleeding or traumatic injury in which hemostasis is impaired due to coagulation factor consumption or occult bleeding from wounds or vascular puncture sites. Frequent monitoring of coagulation studies and platelet counts as well as continual monitoring for bleeding complications is essential for any patient undergoing heparin anticoagulation of the CRRT system. Patients do not require bolusing with heparin before initiation of therapy, because the goal is not to anticoagulate patients but rather to provide regional anticoagulation for the system. If the heparin used for priming is not thoroughly flushed from the system, patients will still receive a small heparin bolus from the priming volume.
Trisodium citrate has been used for many years as an anticoagulant for blood products. It was introduced to CRRT as a regional anticoagulant in the early 1990s. Relatively normal hepatic function is required to metabolize sodium citrate.
Therefore, trisodium citrate has been used to provide anticoagulation of blood in the extracorporeal circuit during CRRT. Citrate affects anticoagulation by binding with calcium and rendering calcium unavailable to the clotting cascade. Since several steps of the clotting cascade are dependent on calcium, the absence of calcium prevents clotting. Once the blood from the extracorporeal circuit is returned to the patient it mixes with the central venous blood which contains calcium and the anticoagulant effect is neutralized. In other words, citrate when returned to the patient from the extracorporeal circuit is no longer an anticoagulant. Generally, calcium is administered to the patient on a continuous basis to prevent any depletion of calcium stores which may occur as a result of citrate binding with calcium and loss of calcium through the extracorporeal circuit.
The prior art has recognized that complications may arise when using trisodium citrate as a regional anticoagulant. The toxicities of this approach include metabolic alkalosis due to citrate accumulation and its subsequent metabolism to bicarbonate, and the effects of reduced systemic ionized calcium. Subjectively the patient may experience palpitations, perioral tingling and stomach cramps. Objective features of citrate toxicity include myocardial depression, arrhythmias and systemic alkalosis which may or may not include an anion gap. Proper surveillance of the rate of citrate administration and monitoring and correction of systemic ionized calcium may obviate these effects. Since normal liver function is required for the metabolism of trisodium citrate, patients with liver disease may be prone to developing citrate toxicity and caution must be exercised in treating these patients with citrate.
Although the use of citrate for regional anticoagulation has been shown to be superior to heparin (4), it often complicates CRRT. A small number of regional citrate anticoagulation protocols offer high solute clearance but also require several customized solutions (5,6,7,8,9,10). Customization of solutions, with subsequent adjustments based on or determined by patient clinical status, expends pharmacy resources in preparing the solutions and increases the risk of error in the preparation of the solutions and their administration (11). This customization of solutions can vary not only between individual patients, but can vary as to the same patient based on that patient's changing clinical status. In addition, if a patient's clinical status changes over the course of treatment, previously prepared solutions may have to be discarded, thereby increasing the costs of treatment. In 2004, two patients receiving CRRT died after potassium chloride, rather than sodium chloride, was mistakenly added to a custom-made dialysate (12,13). As the FDA does not presently require batch testing for quality control, potentially hazardous CRRT solution errors may be unrecognized. In a recent international survey on the management of critically ill ARF patients, the greatest concerns with CRRT included anticoagulation, dialyzer clotting, nursing workload, lack of standards, and cost (3).
The ideal CRRT protocol should provide volume control, metabolic (acid-base and electrolyte) control, and adequate solute clearance, without significant complications related to bleeding or clotting and should be versatile to allow for independent adjustment of the above parameters. Furthermore, the CRRT protocol should use standardized solutions and should not require more than two or three different types of solutions in order to minimize the strain on the compounding pharmacy and healthcare providers. Finally, the CRRT should ideally run with little or no interruption.
The present disclosure provides novel solutions for use with CRRT. In one embodiment, the CRRT protocol is a continuous venovenous hemodiafiltration (CVVHDF) method. CVVHDF provides both diffusive and convective solute clearance and easily maintains a filtration fraction <20% at low blood flow rates and high effluent rates, thereby decreasing the likelihood of filter clotting (14). The present disclosure also provides a simplified set of CRRT solutions for use in CRRT.
Altering the composition of CRRT solutions for each patient proved to be costly, labor-intensive, and error-prone. As a result, we first devised a simplified citrate protocol using 2% trisodium citrate delivered as replacement fluid at 250 ml/hr (citrate 17.5 mmol/hr), with a standardized normal saline dialysate delivered at 1000 ml/hr (15). However, this method could not provide higher effluent rates without also causing severe metabolic complications.
In one embodiment, a bicarbonate-based dialysate and a dilute citrate solution used for both anticoagulation and replacement fluid are disclosed. The citrate solution provides adequate metabolic control, a high ultrafiltration rate, and effective regional anticoagulation without requiring customization based on the clinical status of an individual patient.